Significant improvements in the treatment of cystic fibrosis (CF) have occurred over the past 30 years. In particular, drug delivery via inhalation aerosols to treat the lungs directly has improved outcomes and reduced side effects from common therapies. However, the efficacy inhaled therapies is dramatically reduced in CF patients because of airway obstruction, viscous mucus transport barrier within the airways, and extensive degradation and metabolism of inhaled drug prior to exerting its pharmacological action. Often drugs will not reach the intended target before their activity has been reduced or eliminated. Poor efficiencies lead to extended dosing times and decreased patient compliance. The lack of drug delivery innovation applied to therapies for the treatment of cystic fibrosis is surprising given the level of investigation of the barriers to treatment. The long term objectives are to overcome these barriers and achieve critical improvements in CF therapy. The CENTRAL HYPOTHESIS of the proposed research is that novel functionalized particles will facilitate sustained release of model therapeutic agents with relevance to diffusion and penetration through cystic fibrosis mucus barriers when administered as an aerosol. Our preliminary data have demonstrated that (1) the novel particles can be loaded with a range of therapeutics, (2) they can be prepared as respirable aerosols, (3) significantly enhanced mucus permeation can be achieved using these particles and (4) they can achieve sustained release of drug while avoiding alveolar macrophage clearance. These exciting preliminary data, strongly support the rationale and feasibility of the proposed approach. The main objective of the proposed research is to develop, synthesize, characterize, and evaluate novel particle carrier systems that simultaneously allow controlled lung deposition, avoidance of lung clearance mechanisms, and enhanced transport in CF disease. These systems will provide sustained high drug concentrations delivered directly to the site of action and will therefore facilitate significant improvements in drug and gene therapies in CF, prolonging survival and enhancing quality of life. Therefore, the SPECIFIC AIMS of this project is to (i) Prepare drug loaded functional particles suitable for inhalation via a dry powder aerosolization and targeted lung deposition, (ii) Characterize Drug Release and Delivery Performance of Particles for CF Therapy in vitro and in biological models relevant to CF disease, and (iii) Evaluate in vivo efficacy of sustained release pulmonary delivery system versus immediate release aerosols. The results of the proposed work will be used to design novel approaches for the aerosol treatment of CF lung disease. The proposed studies will fill important gaps in our understanding of the systems of sustained release pulmonary drug delivery and subsequently how controlled administration of drug and gene therapies may impact CF treatment strategies. These R03 feasibility studies, initiate a long term goal of applying drug delivery approaches to CF therapy. [unreadable] [unreadable] [unreadable]